Schizophrenia is a mental illness having a high incidence of about 1% of the entire population. In most cases, convalescence is inferior and patients and their families are forced to suffer from a great burden over a long period of time. To avoid this, many studies have been done as to the etiology of schizophrenia, development of therapeutic drugs thereof and the like.
The first hypothesis proposed on the etiology of schizophrenia was an excess dopaniine hypothesis. Based on this hypothesis, various compounds having a dopamine receptor inhibitory action have been developed as antipsychotic agents and achieved certain therapeutic effects.
The conditions of schizophrenia include positive symptoms mainly showing delusion, hallucination and the like, negative symptoms mainly showing social withdrawal, emotional torpor and the like, recognition function disorder such as defects of memory, learning disability and the like, and the like. A so-called typical antipsychotic agent centering on inhibition of dopamine receptor is comparatively effective on positive symptoms but ineffective against negative symptoms and recognition function disorders. When a typical antipsychotic agent is used, extrapyramidal side effects (e.g., dystonia, akathisia, delayed dyskinesia and the like) are inevitably caused by the dopamine receptor inhibitory action. These difficulties suggest a limit on the development of antipsychotic agent based solely on a so-called excess dopamine hypothesis.
In an attempt to solve the above-mentioned problems, antipsychotic agents, namely, serotonin-dopamine antagonist (SDA), having a serotonin receptor inhibitory action as a main action, have been studied and developed instead of dopamine receptor inhibitory action. Representative antipsychotic agents of SDA include risperidone, Seroquel and the like. However, the problems of poor effectiveness against negative symptoms and recognition function disorder or extrapyramidal side effects have not been entirely overcome [American Journal of Psychiatry 151, 825 (1994)].
One of the etiologic hypotheses of schizophrenia that have overtaken the excess dopamine hypothesis and the serotonin/dopamine hypothesis is a functional depression of glutamic acid nerve hypothesis [Trends in Neuroscience 13, 272 (1990)]. This hypothesis has been supported by the facts that (1) phencyclidine (PCP) which is an inhibitor of NMDA (N-methyl-D-aspartic acid) receptor induces mental conditions in human that are similar to schizophrenia with positive symptoms and negative symptoms [American Journal of Psychiatry 135, 1081 (1978), ibid. 148, 1301 (1991)], (2) cerebral cortex of schizophrenia patients shows lower reactivity of glutamic acid nervous system [Neuroscience Letters 121, 77 (1991)], (3) the number of NMDA receptors also present in the glutamic acid nervous system shows compensatory increase [Life Science 55, 1683 (1994)], (4) NMDA receptor agonists, such as glycine, D-cycloserine and the like, are effective for ameliorating the negative symptoms of schizophrenia [British Journal of Psychiatry 169, 610 (1996), American Journal of Psychiatry 152, 1213 (1995), ibid. 151, 1234 (1994)], and the like.
Clozapine and olanzapine are atypical antipsychotic agents characterized by their effectiveness against positive symptoms as well as negative symptoms of schizophrenia [Psychopharmacology 63, 51 (1992), Neuropsychopharmacology 14, 111(1996)]. These atypical antipsychotic agents suppress abnormal behaviors induced in test animals [Psychopharmacology 120, 67 (1995), ibid, 129, 79 (1997), Pharmacology, Biochemistry and Behavior 47, 579 (1994)] and abnormal physiological function [Psychopharmacology 111, 339 (1993), Journal of Pharmacology and Experimental Therapeutics 271, 787 (1994)] by the functional depression of the glutamic acid nervous system by NMDA receptor inhibitors such as PCP and MK-801 (dizocilpine maleate), and their inhibitory capability is frequently stronger than that of typical antipsychotic agents. In other words, the superior clinical effects of the atypical antipsychotic agent may be ascribed to amelioration of functional depression of glutamic acid nervous system in addition to conventional dopamine receptor inhibitory action and serotonin receptor inhibitory action.
The neurophysiological function abnormalities induced by an NMDA receptor inhibitor includes NMDA receptor inhibitor-induced neurotoxicity [Archive of General Psychiatry 52, 998 (1995)], and MK-80 1-induced neurotoxicity has been studied profoundly. This neurotoxic action can be inhibited by varioius antipsychotic agents, wherein the inhibitory action is stronger in clozapine and olanzapine that are atypical antipsychotic agents than in haloperidol and the like that are typical antipsychotic agents [Schizophrenia Research 15, 57 (1995), ibid. 21, 33 (1996)]. Using this MK-801-induced neurotoxic action as an index, an antipsychotic agent having an ameliorating action of functional depression of glutamic acid nervous system, that is one of the characteristics of clozapine and olanzapine, can be screened for. In addition, an MK-801-induced neurotoxic action is also considered a model of recognition function disorder observed in various diseases such as Alzheimer's disease and the like [Brain Research--Brain Research Reviews, 20, 250-267 (1995)], and a compound capable of inhibiting this neurotoxicity is also effective as a therapeutic drug of Alzheimer's disease, manic-depressive illness and the like.
Meanwhile, the use of clozapine is limited, since it induces serious agranulocytosis, though it also shows superior antipsychotic action [New England Journal of Medicine 324, 746 (1991)]. Reduction of the possibility of side effects is also an important aspect in developing an antipsychotic agent. A report has been recently documented that a cation radical generated as a metabolitic intermediate of clozapine may be involved in the mechanism of onset of agranulocytosis [CNS. Drugs 7, 139 (1997)]. It is significant, therefore, to inhibit generation of cation radical to avoid the onset of agranulocytosis.
Heretofore, there are various reports on suitable modification of the chemical structures of clozapine and olanzapine. For example, WO95/17400, WO96/18621, WO96/18623, WO96/18629, WO96/18630 and WO96/19479 disclose dibenzoxazepine compound, Japanese Patent Examined Publication Nos. 42-24513, 42-24514, 43-27404, 45-20909, 45-6822, 46-29861, 48-34599 and 49-40236, and Japanese Patent Unexamined Publication No. 47-4425 disclose dibenzoxazepine or dibenzothiazepine compound, WO93/07143 discloses pyridobenzoxazepine compound, Journal of Heterocyclic Chemistry 31, 1053 (1994) discloses thienobenzoxazepine compound, and Japanese Patent Unexamined Publication No. 63-8378 discloses dibenzothiazapine compound.
In addition, benzothiophene compound is disclosed in, for example, Japanese Patent Unexamnined Publication Nos. 52-87196 and 51-76296 with regard to 1,2,3,4-tetrahydrobenzothieno[2,3-b][1,5]benzodiazepine derivative.
However, these compounds have remotely overcome the problems of effectiveness against negative symptoms and recognition function disorder, extrapyramidal side effects and the like, and activation of function of glutamic acid nervous system of the compounds of clozapine and olanzapine having suitably modified chemical structures has not been reported.